US6673944B2 - Preparation of warfarin sodium from warfarin acid - Google Patents
Preparation of warfarin sodium from warfarin acid Download PDFInfo
- Publication number
- US6673944B2 US6673944B2 US09/794,212 US79421201A US6673944B2 US 6673944 B2 US6673944 B2 US 6673944B2 US 79421201 A US79421201 A US 79421201A US 6673944 B2 US6673944 B2 US 6673944B2
- Authority
- US
- United States
- Prior art keywords
- sodium
- warfarin
- temperature
- ethanol
- less
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
- C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
Definitions
- This invention relates to the preparation of warfarin sodium. Specifically, the invention relates to the direct preparation of pure warfarin sodium from warfarin acid at low temperature without decomposition using a polar organic solvent and an inorganic base.
- Warfarin sodium known by the chemical name 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one sodium salt, is a well established, widely used oral anticoagulant and rodenticide. See, for example, U.S. Pat. No. 4,113,744 issued Sep. 12, 1978.) Warfarin sodium and its 2-ropanol clathrate are marketed under various commercial names like Coumadin; Marevan; Prothromadin; Tintorane; Warfarin sodium; Warfilone; Waran.
- warfarin sodium prepared by existing methods often has as undesirable slight yellow color.
- U.S. Pat. No. 3,077,481 U.S. Pat. No. 3,192,232 describes aprocess for preparing warfarin sodium and warfarin potassium salts by reacting a slurry or warfarin acid in acetone-water with less than an equivalent of sodium hydroxide or potassium hydroxide in water at room temperature.
- the solution of the crude salt is purified by stirring with active charcoal and isolating of the salt by evaporation to dryness, spray drying, or drum drying.
- U.S. Pat. No. 3,246,013 also emphasizes the difficulties encountered with the preparation of a high purity warfarin sodium. This patent discloses that the removal of the 2-propanol solvent from warfarin sodium 2-propanol clathrate cannot be achieved even with heating at 100° C. over P 2 O 5 for 3-5 hours in vacuum (0.1 mm Hg).
- U.S. Pat. No. 3,077,481 further discloses that heating the clathrate at higher temperatures (145° C.) in air at reduced pressure for prolonged time periods (24 hours) results in undesirable decomposition. Also, heating at still higher temperatures (230° C.), while successfully removing 2-propanol from the clathrate, results in rapid decomposition.
- U.S. Pat. No. 2,765,321 to Schroeder et al. describes a process of preparing crystalline warfarin sodium by reacting an aqueous sodium hydroxide solution with an excess of warfarin acid, followed by removal of the excess acid by addition of ethanol and filtration. Pure warfarin sodium is obtained only after a salting out procedure using lithium chloride addition into the ethanol-water solution of the warfarin sodium salt, cooling and recovering the precipitated warfarin sodium by filtration.
- U.S. Pat. No. 2,777,859 to Link et al. describes a process of preparing an aqueous solution of warfarin alkali metal derivatives by adding an aqueous alkali metal hydroxide to an excess of water wet warfarin acid, warming and removing the excess of warfarin acid by filtration.
- Ohnishi et al. have described a method for preparing warfarin alkali metal salts by dissolving warfarin acid in an aqueous solution containing an equivalent amount of the respective alkali metal hydroxide (lithium, sodium, potassium, rubidium and cesium).
- the respective alkali metal hydroxide lithium, sodium, potassium, rubidium and cesium.
- warfarin sodium in most common polar solvents makes isolation difficult. This is further hampered by the immediate conversion of warfarin sodium to warfarin sodium 2-propanol clathrate when 2-propanol is used as a solvent;
- Warfarin sodium tends to decompose in the presence of water and excess alkalinity, particularly as the temperature is increased;
- the invention is a method for producing warfarin sodium from warfarin acid in a direct, efficient, and industrially feasible manner.
- the method involves reacting warfarin acid with a volatalizable inorganic base, preferably sodium carbonate or sodium bicarbonate, in a stabilizing substantially anhydrous polar organic solvent such as ethanol at low temperature. Further purification and isolation is also conducted at moderate temperatures.
- This invention solves a problem in the prior art where gel formation accompanies evaporation of the solvent during the preparation of warfarin sodium. In the present invention, gel formation is avoided.
- the invention provides advantages not previously appreciated by providing a method for producing pure warfarin sodium wherein the reaction and filtration are conducted at ambient temperature. Furthermore, azeotropic distillation is eliminated entirely.
- the invention offers an unforeseen advantage by conducting the final drying in conventional equipment using hot water or low pressure steam as a heating source.
- the invention is particularly advantageous in that warfarin sodium is not exposed to temperatures in excess of 100° C. which has been found to cause unfavorable decomposition.
- This invention is in a crowded and mature art, but achieves the objective of a simple rapid production of warfarin sodium in an efficient, industrially feasible manner without cumbersome purification steps.
- the invention differs from the prior art in modifications which were not previously known or suggested by using absolute ethanol as solvent and conducting the reaction and purification steps at low temperatures.
- the present invention arises out of a need for a synthesis of warfarin sodium at low temperature. It was found that decomposition of the warfarin sodium occurs when produced by methods requiring elevated temperatures. Furthermore, in the presence of strong bases such as sodium hydroxide and sodium alkoxides normally used for the preparation of warfarin sodium, the warfarin sodium product decomposes, especially at elevated temperatures.
- volatilizable base refers to a base having a conjugate acid which is either gaseous or which decomposes to water and/or a gas upon neutralization.
- volatilizable bases include carbonates and bicarbonates which, upon neutralization, yield carbonic acid that subsequently decomposes into gaseous carbon dioxide and water. It should be recognized that, when specific reference to sodium carbonate or sodium bicarbonate is made herein, other volatilizable bases may be similarly used.
- warfarin sodium during reaction could be avoided by using sodium carbonate or sodium bicarbonate as the volatilizable base and absolute ethanol as solvent.
- This combination surprisingly allows for the reaction to occur at low temperatures preferably of ⁇ 50° C., and more preferably at temperatures ranging from about 25° C. to about 35° C.
- the pH is controlled during work-up by adding small amounts of acids, including warfarin acid.
- the preliminarily isolated warfarin sodium powder is preferably ground to a powder prior to final drying. This allows for the complete drying of the product at relatively low temperatures, preferably less than 70° C., yielding a free flowing powder free of ethanol with excellent yields.
- the basic steps involved in preparing warfarin sodium according to the invention are reacting warfarin acid with a volatalizable base, preferably from sodium carbonate and sodium bicarbonate, in a polar organic solvent, preferably absolute ethanol, removing insoluble salts by filtration, and adjusting the pH to a value of from about 7.8 to about 8.1.
- a volatalizable base preferably from sodium carbonate and sodium bicarbonate
- a polar organic solvent preferably absolute ethanol
- the solvent may be evaporated at low temperature until a heavy syrup is obtained, the resulting syrup poured into trays and additional ethanol evaporated in a drying oven at a temperature of less than about 100° C., preferably less than about 70° C.
- a drying oven at a temperature of less than about 100° C., preferably less than about 70° C.
- the solid is ground to a fine powder, preferably passing through a 60 mesh screen and then returned to the oven to complete drying at temperatures less than about 100° C. It has been observed using existing methods that further evaporation of solvent from the syrup results in gel formation. Solidification of the gel may be accomplished only using more severe heating and mechanical treatment, which may result in decomposition of the warfarin sodium.
- Sodium carbonate is preferably used in excess, preferably as a fine powder, in order to obtain a complete reaction at low temperature in a short reaction time.
- a lower salt to warfarin ratio results in less decomposition but a slower reaction.
- the preferred ratio of molar equivalents of sodium carbonate to warfarin acid was found to be between about 1.1 to 1.5:1.
- High purity warfarin sodium is obtained when the product is precipitated by evaporation of the solvent to dryness at a low temperature, preferably less than about 70° C., and more preferably at less than about 50° C.
- warfarin sodium is advantageous to grind the warfarin sodium through a mesh screen before completion of drying in order to accelerate the evaporation of imprisoned solvent in the crystals and completely remove the ethanol.
- the pH of the filtrate was measured and adjusted to a range of from about 7.8 to about 8. 1.
- the solvent was then removed by evaporation of a temperature of less than 50° C. and under vacuum until a heavy syrup is reached. (About 80 to 90% of ethanol removal.)
- the heavy syrup was then poured into trays and evaporation continued in a vacuum oven until the solid was dry.
- the solid was then removed from the vacuum oven, ground to a fine powder through a 60 mesh screen, and returned back into the trays which were placed in the oven to complete the drying process.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/794,212 US6673944B2 (en) | 2001-02-28 | 2001-02-28 | Preparation of warfarin sodium from warfarin acid |
BR0116918-1A BR0116918A (pt) | 2001-02-28 | 2001-12-28 | Preparação de warfarin sódico a partir do ácido de warfarin |
EP01991574A EP1363894B1 (de) | 2001-02-28 | 2001-12-28 | Herstellung von warfarin-natrium aus warfarin-säure |
ES01991574T ES2239169T3 (es) | 2001-02-28 | 2001-12-28 | Preparacion de warfarina sodica a partir de warfarina acida. |
JP2002569825A JP2004520427A (ja) | 2001-02-28 | 2001-12-28 | ワルファリン酸からのワルファリンナトリウムの調製 |
IL15755301A IL157553A0 (en) | 2001-02-28 | 2001-12-28 | Preparation of warfarin sodium from warfarin acid |
MXPA03007768A MXPA03007768A (es) | 2001-02-28 | 2001-12-28 | Preparacion de sodio de warfarina de acido de warfarina. |
PCT/US2001/050512 WO2002070505A1 (en) | 2001-02-28 | 2001-12-28 | Preparation of warfarin sodium from warfarin acid |
AT01991574T ATE289997T1 (de) | 2001-02-28 | 2001-12-28 | Herstellung von warfarin-natrium aus warfarin- säure |
CNA018229026A CN1492862A (zh) | 2001-02-28 | 2001-12-28 | 从华法令酸制备华法令钠的方法 |
RU2003129001/04A RU2003129001A (ru) | 2001-02-28 | 2001-12-28 | Получение варфарината натрия из варфариновой кислоты |
CA002438407A CA2438407A1 (en) | 2001-02-28 | 2001-12-28 | Preparation of warfarin sodium from warfarin acid |
DE60109212T DE60109212T2 (de) | 2001-02-28 | 2001-12-28 | Herstellung von warfarin-natrium aus warfarin-säure |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/794,212 US6673944B2 (en) | 2001-02-28 | 2001-02-28 | Preparation of warfarin sodium from warfarin acid |
Publications (2)
Publication Number | Publication Date |
---|---|
US20020120157A1 US20020120157A1 (en) | 2002-08-29 |
US6673944B2 true US6673944B2 (en) | 2004-01-06 |
Family
ID=25162028
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/794,212 Expired - Fee Related US6673944B2 (en) | 2001-02-28 | 2001-02-28 | Preparation of warfarin sodium from warfarin acid |
Country Status (13)
Country | Link |
---|---|
US (1) | US6673944B2 (de) |
EP (1) | EP1363894B1 (de) |
JP (1) | JP2004520427A (de) |
CN (1) | CN1492862A (de) |
AT (1) | ATE289997T1 (de) |
BR (1) | BR0116918A (de) |
CA (1) | CA2438407A1 (de) |
DE (1) | DE60109212T2 (de) |
ES (1) | ES2239169T3 (de) |
IL (1) | IL157553A0 (de) |
MX (1) | MXPA03007768A (de) |
RU (1) | RU2003129001A (de) |
WO (1) | WO2002070505A1 (de) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008044246A2 (en) * | 2006-10-10 | 2008-04-17 | Matrix Laboratories Ltd | A process for the preparation of warfarin sodium |
WO2011060944A2 (en) | 2009-11-20 | 2011-05-26 | Gp Pharm, S.A. | Active pharmaceutical ingredient capsules and polyunsaturated fatty acid esters |
WO2011145007A1 (en) | 2010-05-20 | 2011-11-24 | Alembic Pharmaceuticals Limited | A process for the preparation of amorphous warfarin sodium |
WO2011143747A1 (en) * | 2010-05-20 | 2011-11-24 | Apotex Pharmachem Inc. | Polymorphic forms of warfarin potassium and preparations thereof |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8327137B1 (en) * | 2005-03-25 | 2012-12-04 | Advanced Micro Devices, Inc. | Secure computer system with service guest environment isolated driver |
US7259185B2 (en) | 2005-06-15 | 2007-08-21 | Morton Grove Pharmaceuticals, Inc. | Stable warfarin sodium liquid formulation and method of making same |
Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2427578A (en) | 1945-04-02 | 1947-09-16 | Wisconsin Alumni Res Found | 3-substituted 4-hydroxycoumarin and process of making it |
US2752360A (en) | 1953-03-23 | 1956-06-26 | S B Penick & Company Inc | Improvement in the manufacture of 3-substituted 4-hydroxycoumarins |
US2765321A (en) | 1955-05-27 | 1956-10-02 | Wisconsin Alumni Res Found | Process of making crystalline warfarin sodium |
US2777859A (en) | 1953-02-05 | 1957-01-15 | Wisconsin Alumni Res Found | Warfarin-alkali metal derivatives and processes of preparing the same |
US3077481A (en) | 1961-02-21 | 1963-02-12 | Wisconsin Alumni Res Found | Warfarin sodium |
FR1397213A (fr) | 1963-05-14 | 1965-04-30 | Frosst & Co Charles E | Nouveau procédé de préparation de la warfarine-sodium |
US3192232A (en) | 1961-02-21 | 1965-06-29 | Wisconsin Alumni Res Found | Warfarin alkali metal derivative process |
US3239529A (en) | 1962-03-01 | 1966-03-08 | Wisconsin Alumni Res Found | Resolution of warfarin and marcoumar |
US3246013A (en) | 1963-02-15 | 1966-04-12 | Wisconsin Alumni Res Found | Preparation of crystalline warfarin sodium-isopropyl alcohol complex |
US4113744A (en) | 1974-08-13 | 1978-09-12 | Nasri W. Badran | Microcrystalline 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin (warfarin) and methods of making |
US4818297A (en) | 1981-10-29 | 1989-04-04 | Gebruder Lodige Maschinenbau-Gesellschaft | Process for removing solvents from bulk material |
US4826689A (en) | 1984-05-21 | 1989-05-02 | University Of Rochester | Method for making uniformly sized particles from water-insoluble organic compounds |
WO1997003062A1 (en) | 1995-07-13 | 1997-01-30 | The Du Pont Merck Pharmaceutical Company | A novel asymmetric synthesis of r and s warfarin and its analogs |
WO1997024347A1 (en) | 1995-12-28 | 1997-07-10 | Hoechst Corporation | Syntheses based on 2-hydroxyacetophenone |
US5686631A (en) | 1995-07-13 | 1997-11-11 | The Dupont Merck Pharmaceutical Company | Asymmetric synthesis of R and S warfarin and its analogs |
-
2001
- 2001-02-28 US US09/794,212 patent/US6673944B2/en not_active Expired - Fee Related
- 2001-12-28 MX MXPA03007768A patent/MXPA03007768A/es unknown
- 2001-12-28 AT AT01991574T patent/ATE289997T1/de not_active IP Right Cessation
- 2001-12-28 DE DE60109212T patent/DE60109212T2/de not_active Expired - Fee Related
- 2001-12-28 WO PCT/US2001/050512 patent/WO2002070505A1/en active IP Right Grant
- 2001-12-28 RU RU2003129001/04A patent/RU2003129001A/ru unknown
- 2001-12-28 JP JP2002569825A patent/JP2004520427A/ja not_active Withdrawn
- 2001-12-28 CA CA002438407A patent/CA2438407A1/en not_active Abandoned
- 2001-12-28 ES ES01991574T patent/ES2239169T3/es not_active Expired - Lifetime
- 2001-12-28 BR BR0116918-1A patent/BR0116918A/pt not_active IP Right Cessation
- 2001-12-28 IL IL15755301A patent/IL157553A0/xx unknown
- 2001-12-28 EP EP01991574A patent/EP1363894B1/de not_active Expired - Lifetime
- 2001-12-28 CN CNA018229026A patent/CN1492862A/zh active Pending
Patent Citations (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2427578A (en) | 1945-04-02 | 1947-09-16 | Wisconsin Alumni Res Found | 3-substituted 4-hydroxycoumarin and process of making it |
US2777859A (en) | 1953-02-05 | 1957-01-15 | Wisconsin Alumni Res Found | Warfarin-alkali metal derivatives and processes of preparing the same |
US2752360A (en) | 1953-03-23 | 1956-06-26 | S B Penick & Company Inc | Improvement in the manufacture of 3-substituted 4-hydroxycoumarins |
US2765321A (en) | 1955-05-27 | 1956-10-02 | Wisconsin Alumni Res Found | Process of making crystalline warfarin sodium |
US3077481A (en) | 1961-02-21 | 1963-02-12 | Wisconsin Alumni Res Found | Warfarin sodium |
US3192232A (en) | 1961-02-21 | 1965-06-29 | Wisconsin Alumni Res Found | Warfarin alkali metal derivative process |
US3239529A (en) | 1962-03-01 | 1966-03-08 | Wisconsin Alumni Res Found | Resolution of warfarin and marcoumar |
US3246013A (en) | 1963-02-15 | 1966-04-12 | Wisconsin Alumni Res Found | Preparation of crystalline warfarin sodium-isopropyl alcohol complex |
FR1397213A (fr) | 1963-05-14 | 1965-04-30 | Frosst & Co Charles E | Nouveau procédé de préparation de la warfarine-sodium |
GB1056291A (en) * | 1963-05-14 | 1967-01-25 | Frosst & Co Charles E | Improved process for preparing sodium warfarin |
US4113744A (en) | 1974-08-13 | 1978-09-12 | Nasri W. Badran | Microcrystalline 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin (warfarin) and methods of making |
US4818297A (en) | 1981-10-29 | 1989-04-04 | Gebruder Lodige Maschinenbau-Gesellschaft | Process for removing solvents from bulk material |
US4826689A (en) | 1984-05-21 | 1989-05-02 | University Of Rochester | Method for making uniformly sized particles from water-insoluble organic compounds |
WO1997003062A1 (en) | 1995-07-13 | 1997-01-30 | The Du Pont Merck Pharmaceutical Company | A novel asymmetric synthesis of r and s warfarin and its analogs |
US5686631A (en) | 1995-07-13 | 1997-11-11 | The Dupont Merck Pharmaceutical Company | Asymmetric synthesis of R and S warfarin and its analogs |
US5856525A (en) | 1995-07-13 | 1999-01-05 | Dupont Pharmaceuticals Company | Asymmetric R and S warfarin and its analogs |
WO1997024347A1 (en) | 1995-12-28 | 1997-07-10 | Hoechst Corporation | Syntheses based on 2-hydroxyacetophenone |
US5696274A (en) | 1995-12-28 | 1997-12-09 | Hoechst Celanese Corporation | Syntheses based on 2-hydroxyacetophenone |
Non-Patent Citations (25)
Title |
---|
"Warfarin Sodium", Pharmaceutical Manufacturing Encyclopedia, 2<nd >Ed., vol. 2, 1988, pp. 1590-1591. |
"Warfarin Sodium", Pharmaceutical Manufacturing Encyclopedia, 2nd Ed., vol. 2, 1988, pp. 1590-1591. |
Bush et al, "High yield Synthesis of Warfarin and Its Phenolic Metablites: New Compounds", Journal of Pharmaceutical Science, vol. 72, No. 7, pp. 830-831, Jul. 1983. |
Demir, Ayhan S. et al, Enantioselective Synthesis of 4-Hydroxy-3-(3-Oxo-1-Phenyl Butyl)-2H-1-Benzopyran-2-One (Warfarin), Turk. J. Chem, 1996, pp. 139-145. |
Finn, Sidney Louis, Thermogravimetric Analysis of Sodium Warfarin Isopropanol Clathrate (8:4:0), Diss. Abstr. Int. B 1978, 38 (12, Pt. 1), 5951. |
Gao, Danchen, et al., Use of Solution Calorimetry to Determine the Extent of Crystallinity of Drugs and Excipients, International Journal of Pharmaceutics 151, 1997, pp. 183-192. |
Gao, Danchen, Physical Chemical Stability of Warfarin Sodium, AAPS Pharmaci 2001; pp. 1-8. |
Hiskey et al, "Clathrates of Sodium Warfarin" Journal of Pharmaceutical Science, 1965, pp. 1298-1302. |
Ikawa et al, "Studies on 4-Hydroxycoumarins. V. The Condensation of alpha, beta-Unsaturated Ketones with 4-Hydroxycoumarin", Journal of American Chemical Society, 1944, pp. 902-906. |
Ikawa et al, "Studies on 4-Hydroxycoumarins. V. The Condensation of α, β-Unsaturated Ketones with 4-Hydroxycoumarin", Journal of American Chemical Society, 1944, pp. 902-906. |
Ivanov, "New Efficient Catalysts in the Synthesis of Warfarin and Acenocoumarol", Arch. Pharm (Weinheim), 1990, 323, pp. 521-522. |
Joshi, C.G., et al., Studies in the Synthesis of Warfarin [3-( -Acetonylbenzyl)-4-hydroxycoumarin] Indian J. Technol., 1972, pp. 461-462. |
Kleemann & Engel, et al. "Pharmaceutical Substances" 3<rd >Ed (English), p. 2010 (1999). |
Kleemann & Engel, et al. "Pharmaceutical Substances" 3rd Ed (English), p. 2010 (1999). |
Manolov, I., et al., Synthesis and Antimetastic Properties of 4-hydroxy-3(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one (Warfarin), Farmatsiya (Sofia), 1990, pp. 1-6 (English abstract). |
Ohnishi, "Structure-Activity Relationship between the Hydrophobicity of Alkali metal Salts of Warfarin[3-(alpha-Acetonyl-benzyl)-4-hydroxycoumarin] and the Effectiveness of the Taste Response to These Salts in Mice", Biosci. Biotech. Biochem., 59 (6), 995-1001. 1995. |
Ohnishi, "Structure-Activity Relationship between the Hydrophobicity of Alkali metal Salts of Warfarin[3-(α-Acetonyl-benzyl)-4-hydroxycoumarin] and the Effectiveness of the Taste Response to These Salts in Mice", Biosci. Biotech. Biochem., 59 (6), 995-1001. 1995. |
Ozcan, Eyup, et al., Factors Affecting the Reaction Efficiency in Warfarin Synthesis, Marmara Univ. Fen Bilimleri Derg., 1989, pp. 155-167 (Article and citation attached). |
Robinson, Andrea, et al., The First Practical Asymmetric Synthesis of R and S-Warfarin, Tetrahedron Lett., 1996, pp. 8321-8324. |
Seidman et al, "Studies on 4-Hydroxycoumarins. X. Acylation of 3-(alpha-Phenyl-beta-acetylethyl)-4-hydroxycoumarin", Journal of American Chemical Society, Nov. 1950, pp. 5193-5195. |
Seidman et al, "Studies on 4-Hydroxycoumarins. X. Acylation of 3-(α-Phenyl-β-acetylethyl)-4-hydroxycoumarin", Journal of American Chemical Society, Nov. 1950, pp. 5193-5195. |
The Merck Index, 12<th >Edition, 10174. "Warfarin", pp. 1715 (1996). |
The Merck Index, 12th Edition, 10174. "Warfarin", pp. 1715 (1996). |
Xu, X.Y., Identification of Principal Components of Clathrate and Complex with Infrared Spectral Subtraction Method, Chinese Journal of Pharmaceutical Analysis (China), V. 17 (Mar. 1997), pp. 87-89 (English abstract). |
Yang, Tsang, et al., Synthesis of Anticoagulants, Dicumarol and Warfarin, T'ai-wan K'o Hseu, 1984, pp. 1-7 (Citation only attached). |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008044246A2 (en) * | 2006-10-10 | 2008-04-17 | Matrix Laboratories Ltd | A process for the preparation of warfarin sodium |
WO2008044246A3 (en) * | 2006-10-10 | 2009-09-24 | Matrix Laboratories Ltd | A process for the preparation of warfarin sodium |
WO2011060944A2 (en) | 2009-11-20 | 2011-05-26 | Gp Pharm, S.A. | Active pharmaceutical ingredient capsules and polyunsaturated fatty acid esters |
WO2011145007A1 (en) | 2010-05-20 | 2011-11-24 | Alembic Pharmaceuticals Limited | A process for the preparation of amorphous warfarin sodium |
WO2011143747A1 (en) * | 2010-05-20 | 2011-11-24 | Apotex Pharmachem Inc. | Polymorphic forms of warfarin potassium and preparations thereof |
Also Published As
Publication number | Publication date |
---|---|
US20020120157A1 (en) | 2002-08-29 |
DE60109212D1 (de) | 2005-04-07 |
MXPA03007768A (es) | 2004-11-12 |
EP1363894B1 (de) | 2005-03-02 |
DE60109212T2 (de) | 2006-01-12 |
RU2003129001A (ru) | 2005-02-27 |
ES2239169T3 (es) | 2005-09-16 |
EP1363894A1 (de) | 2003-11-26 |
IL157553A0 (en) | 2004-03-28 |
ATE289997T1 (de) | 2005-03-15 |
CA2438407A1 (en) | 2002-09-12 |
CN1492862A (zh) | 2004-04-28 |
BR0116918A (pt) | 2004-04-27 |
JP2004520427A (ja) | 2004-07-08 |
WO2002070505A1 (en) | 2002-09-12 |
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